Phenytoin-Folic Acid Interaction

Abstract

Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.

Effect of folic acid and vitamin B12 administration on phenytoin induced toxicity in rats

“…Phenytoin is reported to cause change in the metabolism of folate and vitamin B 12 (11). However, the effect of vitamin B 12 supplementation did not influence the toxicity of phenytoin as the raised level of the enzymes activities, which were raised by phenytoin remained almost the same.…”

“…Phenytoin administration has been reported to result in altered folate and vitamin B 12 metabolism. Both serum and red cell levels of these vitamins have been altered in over 50% of patients on phenytoin therapy (10,11). Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation and folic acid supplementation in folate deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough (11).…”

“…Several suggestions have been made in an attempt to deduce the mechanism by which phenytoin alter folate metabolism (11,12). Porter and Meldrum (13), proposed that phenytoin causes mal-absorption of dietary folate by inhibiting a conjugase, an enzyme that converts the polyglutamate form of folate to the absorbable monoglutamate.…”

“…It has been recommended that folic acid supplementation should be initiated each time phenytoin therapy commences. This is because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency and better seizure control with no perturbation of phenytoin pharmacokinetics (11).…”

Oral Tegafur/folinic acid chemotherapy decreases phenytoin efficacy

“…The patient developed inefficacy of the antiepileptic treatment due to the drug interaction of folinic acid from his chemotherapy regimen and phenytoin. The metabolic interaction between folinic or folic acid and phenytoin causing a decrease in phenytoin plasma levels is a well-known pharmacokinetic interaction (Lewis et al, 1995). It has been described that this interaction already takes place after daily intake of 15 mg folic acid during 2 weeks (Berg et al, 1983).…”